Immunologic Profiles of Distinct Cognitive Trajectories in Adultswith Perinatal HIV

围产期 HIV 感染者的不同认知轨迹的免疫学特征

• 批准号: 10206044
• 负责人: Payal Patel
• 金额: $ 17.19万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-11 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206044
• 关键词: 21 year old; Address; Adult; Affect; Age; Area; Biological; Biological Markers; Biology; Biometry; Birth; Brain; CD14 gene; CD8-Positive T-Lymphocytes; Cerebrospinal Fluid; Cerebrum; Child; Childhood; Clinical; Cognition; Cognitive; Communicable Diseases; Complex; Connecticut; Cross-Sectional Studies; Cytometry; Data; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Doctor of Philosophy; Enrollment; FCGR3B gene; Flow Cytometry; Foundations; Frequencies; Funding; Future; Goals; HIV; HIV-1; HIV-associated cognitive impairment; HLA-DR Antigens; Health; Heterogeneity; Immune; Immune response; Immunologic Markers; Immunologics; Impaired cognition; Impairment; Individual; Intervention; Knowledge; Light; Link; Long-Term Survivors; Longitudinal cohort study; Mentors; Mentorship; Methods; Modeling; Morbidity - disease rate; Nervous System Trauma; Neuraxis; Neurodevelopmental Impairment; Neurologic; Neurological outcome; Neurologist; Neuronal Injury; Outcome; Participant; Pathogenesis; Perinatal; Peripheral; Plasma; Population; Prevalence; Prevention; Productivity; Prognosis; Prospective Studies; Protocols documentation; Psyche structure; RNA; Research; Risk Factors; Southeastern Asia; Subgroup; T-Cell Activation; Techniques; Time; Training; Viral; Viral Load result; Youth; age group; analytical method; antiretroviral therapy; base; cognitive performance; cohort; comorbidity; early adolescence; experience; imaging biomarker; immune activation; improved; longitudinal analysis; monocyte; mortality; neuroAIDS; neurocognitive test; neurofilament; neuroimaging; novel; outcome prediction; perinatal HIV; peripheral blood; preservation; prevent; resilience; tool; trafficking; treatment effect; trend; white matter; young adult

Over 60,000 young adults are living with HIV in the US today, many of whom acquired HIV at birth. This group of adults with perinatally acquired HIV (pHIV) has not seen improvements in the prevalence of HIV- related co-morbidities, including poor cognitive outcomes. Despite this trend, little is known about the prognosis and pathogenesis of pHIV-related cognitive impairment in adulthood. Cognitive dysfunction occurs in up to half of individuals living with HIV, and is directly associated with immune activation in adults with horizontally acquired HIV (hHIV). In contrast, CD8+ T-cell and monocyte activation in our cohort of children with pHIV in Southeast Asia correlates with better cognitive scores suggesting an adapted immune-host response in those who are long-term survivors of pHIV. This adapted state has not been well studied. The goal of our proposed study is to address key gaps in our understanding of 1) cognitive trajectories and 2) biomarkers of cognitive resilience in adults with pHIV, through a recently initiated longitudinal cohort study of adults with pHIV in Connecticut. We will evaluate 1) cognitive performance and 2) interactions between peripheral and cerebrospinal fluid (CSF) immunologic markers, neuroimaging and cognition using a novel analytic method, group based trajectory modeling. This study will determine the prognosis of cognitive impairment and further characterize the biologic underpinnings of cognitive resilience as potential neuroprotective targets in adults with pHIV. The candidate is a pediatric neurologist with specialized training in neuro-infectious diseases. Dr. Patel is committed to improving our understanding of the pathogenesis of and treatment for poor neurologic outcomes following pHIV. The proposal will capitalize on Dr. Patel's prior training and mentored research experience in group based trajectory analysis of longitudinal cognitive data in children with pHIV, while enabling her to build expertise in 1) flow cytometry methods and analyses, 2) utilizing diffusion tensor imaging as a research tool, and 3) dual trajectory analysis, a complex modeling technique to assess contemporaneous changes in longitudinally acquired biomarker and cognitive data. Dr. Patel has assembled a mentorship committee comprised of leaders in the pathogenesis of neurologic injury in adults with hHIV (Serena Spudich, MD, primary mentor), biomarkers of disease progression in pHIV (Elijah Paintsil, MBChB, co-mentor), and biostatistics and imaging markers of cognitive impairment in pHIV (Robert Paul, PhD, co-mentor). The knowledge and experience gained from this proposal will allow Dr. Patel to successfully compete for R01 funding to further evaluate the pathogenesis and prevention of pHIV-related neurologic morbidity. Her future R01 applications will focus on cerebral HIV compartmentalization in adults with pHIV and analyzing cellular subsets identified in the proposed study as linked to cognitive resilience in CSF using mass cytometry.

今天，有60,000多名年轻人在美国患艾滋病毒，其中许多人出生时就收购了艾滋病毒。 这组具有围产期收购HIV（pHIV）的成年人没有看到患病率的提高 与HIV相关的合并症，包括认知结果差。尽管有这种趋势，但对 成年期与pHIV相关的认知障碍的预后和发病机理。认知功能障碍 发生在多达一半的艾滋病毒的人中，直接与免疫激活有关 水平获得HIV（HHIV）的成年人。相反，我们的CD8+ T细胞和单核细胞激活 东南亚PHIV儿童队列与更好的认知分数相关，表明 在PHIV的长期幸存者中，适应免疫宿主反应。这个改编的状态还没有 经过深入研究。我们拟议的研究的目的是解决我们理解的关键差距 1）认知轨迹和2）成人PHIV的认知弹性生物标志物， 最近开始了康涅狄格州PHIV的成年人的纵向队列研究。我们将评估1） 认知性能和2）外周和脑脊液（CSF）免疫学之间的相互作用 使用新的分析方法，基于组的轨迹建模，标志物，神经影像学和认知。 这项研究将确定认知障碍的预后，并进一步表征生物学 认知弹性的基础作为pHIV成年人的潜在神经保护靶标。 候选人是一名儿科神经科医生，接受了神经感染疾病的专门培训。博士 帕特尔致力于提高我们对贫困的发病机理和治疗的理解 PHIV后神经系统结局。该提案将利用帕特尔博士的先前培训和 在基于小组的纵向认知数据基于小组的轨迹分析中的指导研究经验 PHIV的儿童，同时使她能够在1）流式细胞仪方法中建立专业知识 分析，2）利用扩散张量成像作为研究工具，3）双重轨迹分析，一个 复杂的建模技术，以评估纵向获得的同时变化 生物标志物和认知数据。帕特尔博士已经组建了一个由领导人组成的指导委员会 在HHIV成年人（Serena Spudich，MD，主要导师）的神经系统损伤的发病机理中， PHIV中疾病进展的生物标志物（Elijah Paintsil，MBCHB，Co-Insor），生物统计学和生物统计学和 PHIV认知障碍的成像标记（Robert Paul，PhD，Co-Insor）。知识和 从该提案中获得的经验将使帕特尔博士能够成功竞争R01资金 进一步评估了与pHIV相关的神经系统发病率的发病机理和预防。她的未来R01 应用将重点放在pHIV成人的脑HIV分区并分析细胞 在拟议的研究中鉴定出的子集使用质量细胞仪与CSF中的认知弹性有关。